Hyperactivity of the brain renin-angiotensin system (RAS) participates in the development and maintenance of hypertension in various types of experimental and genetic models of hypertension. ACE2, a newly discovered member of the RAS appears be part of a counter-regulatory pathway buffering the excess of Ang-ll. Evidence of the presence of ACE2 in organs related to cardiovascular (CV) function (e.g. heart, kidney, vessels) and its role in the generation of biologically active peptides supply a rationale for further explorations in the brain in the face of normal and pathophysiological states. In this proposal, we hypothesize that ACE2 is a functional element of the brain RAS and its inhibition leads to the development of hypertension. Taking advantage of our expertise to continuously record and analyze CV function in conscious mice, combined to our ability to manipulate the brain through a panel of physiological, pharmacological and molecular tools, we will address the following questions: 1) What is the anatomical localization and functional role of ACE2 in brain of normal mice and how is it affected by changes in brain RAS components? 2) Does inhibition of ACE2 lead to the development of hypertension and does over-expression of ACE2 in the brain rescue the high blood pressure (BP) phenotype in hypertensive mice? We believe that we possess the better tools to answer these questions. Through a combination of physiological, pharmacological, molecular and gene-targeting approaches we will determine the physiological role of central ACE2 in vivo in the regulation of BP and CV function. Evidence of a role of ACE2 in the regulation of BP could lead to the development of new therapeutics as well as a better utilization of existing therapeutics for the treatment of hypertension and other CV diseases. [unreadable] [unreadable]